Antiproliferative and toxicological properties of drimanes obtained from Drimys brasiliensis stem barks

Fratoni, Eduarda; Athayde, Amanda Ellen de; Machado, Marina da Silva; Zermiani, Tailyn; Venturi, Ivonilce; Santos, Matheus Corrêa dos; Lobato, Fabiane; Filho, Valdir Cechinel; Franchi, Gilberto C.; Nowill, Alexandre E.; Santin, José Roberto; Malheiros, Ângela

doi:10.1016/j.biopha.2018.04.103

Cited by 10 publications

(16 citation statements)

References 24 publications

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“…The structure‐activity relationship studies that can be deduced from these experiments match perfectly to those published by us [28] and Madeiros's group [31] following the cytotoxicity studies on similar compounds. Aldehyde functions in position 8 and 9 are required as demonstrated with compound 9 that presents a low affinity for MCL‐1 with K i =5.26 μM and is not active on BCL‐xL.…”

Section: Resultssupporting

confidence: 82%

“…We have also shown that their reduction, oxidation or cyclisation is detrimental [28] . These results were confirmed by Fratoni et al., [31] who have pointed out that drimane derivatives with similar structures as 1 isolated from Drimys brasiliensis (Winteraceae) are cytotoxic against various myeloid and lymphoid cell lines. Contrarily, drimanes like polygodial 2 that do not possess a cynnamoyl group at C1 are found much less cytotoxic [32,33] …”

Section: Introductionsupporting

confidence: 85%

“…As it has been demonstrated that drimane derivatives are cytotoxic against myeloid and lymphoid cell lines, [31] we intended to associate the cytotoxicity of compounds 5 and 7 to their affinity to anti‐apoptotic members of BCL‐2, and more particularly to MCL‐1 as these proteins are known to play a central role in haematological malignancies tumorigenicity. In vitro tests were realised on 2 haematological cells lines whose dependences to anti‐apoptotic members of BCL‐2 family have been previously characterised [25] .…”

Section: Resultsmentioning

confidence: 99%

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Drimane Derivatives as the First Examples of Covalent BH3 Mimetics that Target MCL‐1

et al. 2021

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Drimane sesquiterpenoid dialdehydes are natural compounds with antiproliferative properties. Nevertheless, their mode of action has not yet been discovered. Herein, we demonstrate that various drimanes are potent inhibitors of MCL‐1 and BCL‐xL, two proteins of the BCL‐2 family that are overexpressed in various cancers, including lymphoid malignancies. Subtle changes in their structure significantly modified their activity on the target proteins. The two most active compounds are MCL‐1 selective and bind in the BH3 binding groove of the protein. Complementary studies by NMR spectroscopy and mass spectrometry analyses, but also synthesis, showed that they covalently inhibit MCL‐1 though the formation of a pyrrole adduct. In addition, cytotoxic assays revealed that these two compounds show a cytotoxic selectivity for BL2, a MCL‐1/BCL‐xL‐dependent cell line and induce apoptosis.

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Section: Resultssupporting

confidence: 82%

Section: Introductionsupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

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Drimane Derivatives as the First Examples of Covalent BH3 Mimetics that Target MCL‐1

et al. 2021

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“…In addition, drimane sesquiterpenoid derivatives linked to phenolic acids such as CPH1 exhibited cytotoxic activity against epidermoid mouth carcinoma (KB), colorectal carcinoma (HCT116) and promyelocytic leukaemia (HL60), 43 as well as against chronic myelogenous leukaemia (K562) and human hepatoma (SMMC‐7721) 44 . Fratoni et al also showed cytotoxic effects with drimane sesquiterpene derivatives linked to phenolic acids against chronic myeloid leukaemia (K562), acute B lymphoblastic (Nalm6), acute promyelocytic leukaemia (NB4), Burkitt's lymphoma (RAMOS) cells, Burkitt's lymphoma (RAJI) and acute T cell leukaemia (MOLT4) cell lines 45,46 . Finally, Menezes et al showed that p ‐coumaric derivatives linked to a long hydrocarbonated chain are promising scaffolds for novel anticancer agents, because it can increase apoptotic cells in the sub‐G1 phase and activate the caspase‐3 enzyme in MOULT‐4 leukaemia cells.…”

Section: Discussionmentioning

confidence: 99%

“…44 Fratoni et al also showed cytotoxic effects with drimane sesquiterpene derivatives linked to phenolic acids against chronic myeloid leukaemia (K562), acute B lymphoblastic (Nalm6), acute promyelocytic leukaemia (NB4), Burkitt's lymphoma (RAMOS) cells, Burkitt's lymphoma (RAJI) and acute T cell leukaemia (MOLT4) cell lines. 45,46 Finally, Menezes et al showed that p-coumaric derivatives linked to a long hydrocarbonated chain are promising scaffolds for novel anticancer agents, because it can increase apoptotic cells in the sub-G1 phase and activate the caspase-3 enzyme in MOULT-4 leukaemia cells. Also, these compounds were more potent than doxorubicin and cisplatin against drug resistant MES-SA-DX5 uterine sarcoma cells.…”

Section: Discussionmentioning

confidence: 99%

Bioguided isolation of a selective compound from Calea phyllolepis leaves against breast cancer cells

Rosa

Borsoi

Conter

et al. 2021

Basic Clin Pharma Tox

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Plants of the Calea genus have been reported to contain lipophilic compounds, such as sesquiterpene lactones, with cytotoxic effect against different cancer cell lines. The aim of this manuscript was to investigate the chemical profile and cytotoxic activity of different fractions from Calea phylolepis leaves on different human cancer cell lines. The fractions were prepared using solvent extraction of increasing polarity, yielding hexane, ethyl acetate and methanolic fractions. All fractions were chemically analysed by thin layer chromatography (TLC), and their cytotoxic activity against HT‐29 (colon adenocarcinoma), MCF‐7 (breast cancer), U‐251MG (malignant glioblastoma) and L929 (mouse fibroblast) cell lines was investigated. Among these, the hexane and ethyl acetate fractions showed higher cytotoxic effects, while the methanolic fraction did not show any cytotoxic effects. The major bioactive compound from the hexane fraction (12.15%) was isolated using chromatographic methods and was identified by nuclear magnetic resonance spectroscopy (NMR) and gas chromatography–mass spectrometry (GC–MS) analysis as 6‐epi‐β‐verbesinol coumarate. This compound showed activity against breast cancer cells (IC50 = 5.8 ± 1.0 μg/ml), similar to etoposide. Furthermore, 6‐epi‐β‐verbesinol coumarate showed low cytotoxicity to normal fibroblast cells, suggesting a high selectivity index (SI = 7.39) against breast cancer cells.

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NA1—115—7, from Zygogynum pancheri, is a new selective MCL-1 inhibitor inducing the apoptosis of hematological cancer cells but non-toxic to normal blood cells or cardiomyocytes

Daressy¹,

Séguy²,

Favre³

et al. 2022

Biomedicine & Pharmacotherapy

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Antiproliferative and toxicological properties of drimanes obtained from Drimys brasiliensis stem barks

Cited by 10 publications

References 24 publications

Drimane Derivatives as the First Examples of Covalent BH3 Mimetics that Target MCL‐1

Drimane Derivatives as the First Examples of Covalent BH3 Mimetics that Target MCL‐1

Bioguided isolation of a selective compound from Calea phyllolepis leaves against breast cancer cells

NA1—115—7, from Zygogynum pancheri, is a new selective MCL-1 inhibitor inducing the apoptosis of hematological cancer cells but non-toxic to normal blood cells or cardiomyocytes

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